Table Of ContentAging and the Heart
Aging and the Heart
A Post-Genomic View
José Marín-García
Director
The Molecular Cardiology and Neuromuscular Institute
Highland Park, New Jersey
Withthecollaboration of
Michael J. Goldenthal
SeniorResearchScientist
TheMolecularCardiologyandNeuromuscularInstitute
HighlandPark,NewJersey
Gordon W. Moe
AssociateProfessor
UniversityofToronto
St.MichaelHospital
Toronto,Canada
JoséMarín-García,M.D.
Director,TheMolecularCardiology
andNeuromuscularInstitute
HighlandPark,NewJersey
ISBN:978-0-387-74071-3 e-ISBN:978-0-387-74072-0
LibraryofCongressControlNumber:2007931956
(cid:2)c 2008SpringerScience+BusinessMedia,LLC
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Preface
Cardiacaging,likeagingingeneral,isacomplexprocessinvolvingnumerouscellularandmolecular
changes,whichalongthewaycontributetotheexpressionofthemultiplephenotypesofaging,“the
differentfaces”ofcardiacaging.Severalplausibletheorieshavebeenconsideredtoexplainaging,
e.g., evolutionary, free radical, and somatic mutation. However, at this time it is most likely that
these different theories are intertwined with each other without a definitive “winner”, reflecting
a mixture of genetic and epigenetic elements found in most aged individuals with cardiovascular
defects. The demonstration in numerous animals models of the dramatic alterations in life span
achieved by gene engineering or lifestyle modifications, such as caloric restriction and exercise,
further underscores the interplay of both genetic and environmental factors in aging, as well their
actingthroughmolecularandsignalingpathwaysoperativeintheheartandthevasculature.
That aging and decreasing heart function occurred together has been amply documented, and
ourcurrentknowledgeofage-associatedcardiacpathologieshasoutpacedourunderstandingofthe
basicmechanismsunderlyingtheseprocesses.Atpresent,Genomic,Proteomic,RecombinantDNA
andothertechniquesareincreasinglybeingappliedtostudycardiaccellsstructuralandfunctional
changes in diverse pathologies, as well as in aging in general, and in the aging heart in particular.
An ever increasing number of animal models have contributed greatly to our understanding of the
multiplepathwaysandmoleculesparticipatinginthedevelopmentofcardiovascularagingdysfunc-
tion and aging-associated diseases. With the availability of the Human Genome Project and novel
andexcitingmoleculartechnologies,theunravelingoftheunderlyingbasicmechanismsofcardiac
aginghavealreadybegun.
Inpreparing thisbookithasbeen our majorobjective topresenteach chapter as clearlyand as
comprehensivelyaspossibleprovidingcurrentinformationavailableontheoriesanddevelopmental
mechanismsofaging,includingbiochemical,cellular,molecular,geneticandepigeneticdata.The
genetic and molecular basis of cardiovascular aging will be thoroughly discussed together with a
comprehensive assessment of the bioenergetic changes occurring in human and animal models of
cardiacaging,diagnosticprogressandfuturetherapeuticmodalities.
Besides presenting a detailed review of the most pertinent investigative works from multiple
sources,wehavealsotriedtoaddasmuchexplanatoryideasandconceptsgeneratedfromourown
workoncardiovascularaging.Furthermore,wehavediscussedwhatinouropinionisthefutureof
this important field, mainly from the standpoint of basic research. Notwithstanding, we have also
acknowledgedthegreatcontributionsfromthepast,andarecertaintheywillcontinueinthefuture
The chapters in this book have been arranged in a way that the readers can to some degree
recognizeandappreciatethecurrentthoughtsandideasontheparticularfield/subject.Furthermore,
wehavetriedtoincludeasmuchaspossibleoriginalandcreativescientificworks,butawareofour
limitationswemustacceptthatthisisaworkstillinprogress.
Wearehopefulthatthisbookwillbeavaluableguidetoagingandtheheartfromapost-genomic
perspective,andalsoanimportantintroductiontonewideasandfutureprogress.Althoughwedonot
expectthatthisbookwillmakeanyoneanexpertinthefield,certainlyitwillprovideaoverall-grasp
vii
viii Preface
of-theoriesandperspectivesthatmayshapethepresentandfutureunderstandingofCardiovascular
Aging.
Finally,IwanttothankDrs.GoldenthalandMoefortheircontribution,fortheirenthusiasmand
fortheirdedicationtomakethisendeavorallworthy.
“............Timewillpass,inevitably
Deathwillfollow,consequently
Afterahealthyandproductiveaging,hopefully”
JoséMarín-García
HighlandPark,NJ
Contents
PartI IntroductiontoaPost-GenomicViewofAgingandtheAgingHeart
1 Post-GenomicViewofAging:Definitions,TheoriesandObservations ............. 3
Overview................................................................. 3
Definitions................................................................ 4
Longevity ................................................................ 4
Gene-LongevityAssociationStudies .......................................... 4
LongevityGenesfromModelSystems ........................................ 8
TheoriesofAging.......................................................... 12
EvolutionaryTheories .................................................... 12
Molecular/GenomeMutations/DeletionsTheory .............................. 14
Wear-andTear-Theories .................................................. 16
(a)FRTA............................................................ 16
(b)Cross-LinkageTheory.............................................. 19
(c)DNA-RepairTheory ............................................... 19
(d)CellularGarbageTheory............................................ 19
(e)TheMembraneTheoryofAging ..................................... 19
(f)TheHayflickTheory ............................................... 19
ReliabilityTheory ....................................................... 19
Neuro-Endocrine/ImmunologicalTheory .................................... 20
HormesisandAging...................................................... 21
GenderIssuesinAging ................................................... 21
AdvancesonAgingandtheGenome........................................ 22
Epidemiology/HumanPopulations............................................ 24
PopulationAging ........................................................ 24
Modifying/DelayingAging ............................................... 25
IsAgingReversible? ..................................................... 26
References................................................................ 26
2 OverviewofCardiovascularAging ............................................ 33
Overview................................................................. 33
Introduction............................................................... 33
BiophysiologyofCVAging ................................................. 34
Mechanisms/SignalingPathwaysintheAgingHeart............................. 35
TelomeresandCVAging ................................................. 35
CellularDamage/CellLoss,MitochondriaandCVAging....................... 37
ROSGenerationandCVAging ............................................ 41
InflammationandCVAging............................................... 45
ix
x Contents
NeuroendocrineMechanismsinCVAging..................................... 45
Adrenergic(andMuscarinic)ReceptorsintheAgingHeart ..................... 46
CardiacGProtein-CoupledReceptors....................................... 47
ThyroidHormone/SERCAintheAgingHeart ................................ 48
Growthhormone(GH)andIGF-1 .......................................... 49
AutophagyandCVAging................................................... 51
CardiacFunctioninAging................................................... 52
GeneticMake-upinCardiacAging ........................................... 52
EpigeneticandEnvironmentalFactorsinCardiacAging.......................... 53
EpidemiologyofCVAgingandPopulationDifferences .......................... 55
AgingisNotaDisease,RatheraRiskFactor ................................... 56
Modifying/DelayingCVAging .............................................. 57
StemCellsandCVAging ................................................. 58
DietaryandLifestyleChange ................................................ 58
Conclusion ............................................................... 58
Summary ................................................................. 59
References................................................................ 60
PartII Methodologies,CardiacPhenotypesandAdaptation
3 MolecularandCellularMethodologies:APrimer............................... 71
Overview................................................................. 71
Introduction............................................................... 71
CellCulture:StudyingIsolatedCardiomyocytesandVascularCellsinAging ........ 72
ObservationsinEndothelialandSmoothMuscleCells ........................... 73
CellandTissueTransfectionandGeneTransferinCardiovascularStudies .......... 74
Knock-outTransgenicAnimalModels ........................................ 77
GeneProfiling:TranscriptomeandProteomicAnalysis........................... 78
ProteomicAnalysis......................................................... 81
DNADamageandMutationsinAging ........................................ 83
TypesofDNADamage ..................................................... 83
MicrosatelliteInstability .................................................. 83
Single-StrandversusDouble-StrandDamage................................. 83
CometAssay.............................................................. 84
DNARepairEnzymesinAging .............................................. 85
MutationAnalysis ......................................................... 87
TelomereAnalysis ......................................................... 88
Cell-EngineeringandTransplantation ......................................... 89
TissueEngineering......................................................... 91
Conclusion ............................................................... 92
Summary ................................................................. 93
References................................................................ 94
4 MolecularandCellularPhenotypesofCardiovascularAging..................... 103
Overview................................................................. 103
Introduction:MorphologicalChangesintheAgingHeart......................... 103
Fibrosis ................................................................ 105
Apoptosis(ProgrammedCellDeath),NecrosisandMyocardialRemodeling......... 106
Mitochondria,ETCandROS ................................................ 110
AutophagyandCardiacAging ............................................... 113
Contents xi
Post-translationalChangesAssociatedwithAging............................... 115
Glycation............................................................ 117
DNADamage ............................................................. 117
TypesofDamage ........................................................ 117
RoleofDNARepair........................................................ 123
MitochondrialDNARepair.................................................. 128
DNARepairandHumanDiseasesofAging .................................... 129
TelomeresandTelomere-relatedProteins ...................................... 131
Conclusion ............................................................... 134
Summary ................................................................. 135
References................................................................ 135
PartIII AgingoftheCardiovasculatureandRelatedSystems
5 AgingoftheVasculatureandRelatedSystems.................................. 149
Overview................................................................. 149
Introduction............................................................... 149
ArterialRemodelingandAging .............................................. 149
EndothelialCellFunctionandRemodeling..................................... 155
RoleofCellSenescence .................................................. 155
MechanismsofCellSenescence......................................... 157
FunctionalEffectsofEndothelialCellSenescence............................. 158
EndothelialAgingandOxidativeStress ..................................... 160
EndothelialDysfunctionisCentraltotheVascularAgingPhenotype .......... 162
AgingandVascularSmoothMuscleCells(SMCs) .............................. 162
MechanismsandSignificanceofVascularSMCSenescence .................... 164
MarkersofSMCinAgingandAging-RelatedDiseases ........................ 165
Thrombosis,FibrinolysisandInflammationinAging ............................ 166
Angiogenesis/NeovascularizationinAging..................................... 168
Conclusion ............................................................... 169
Summary ................................................................. 169
References................................................................ 170
6 AgingandtheCardiovascular-RelatedSystems................................. 181
Overview................................................................. 181
Introduction............................................................... 181
TheAgingImmuneSystem.................................................. 182
AgingandNeurohormonalRegulation......................................... 191
AgingandSkeletalMuscle ................................................ 194
AgingandtheBlood-BrainBarrier ......................................... 196
Conclusion ............................................................... 198
Summary ................................................................. 199
References................................................................ 200
PartIV CardiovascularDiseasesinAging
7 CardiomyopathyandHeartFailureinAging ................................... 209
Overview................................................................. 209
Introduction............................................................... 209
